Ruthenium (II) complexes for the treatment of tumors

ABSTRACT

Ruthenium (II) compounds of formula (I) are useful in the treatment and/or prevention of cancer.

This invention relates to ruthenium(II) compounds, to their use inmedicine, particularly for the treatment and/or prevention of cancer,and to a process for their preparation.

Certain ruthenium(II) complexes have been proposed for use in treatingcancer. For example, U.S. Pat. No. 4,980,473 discloses1,10-phenanthroline complexes of ruthenium(II) and cobalt(III) which aresaid to be useful for the treatment of tumour cells in a subject.

Some other ruthenium(II) and ruthenium(III) complexes which have beenshown to exhibit antitumour activity are mentioned in Guo et al,Inorganica Chimica Acta, 273 (1998), 1-7, specificallytrans-[RuCl₂(DMSO)₄], trans-[RuCl₄(imidazole)₂]⁻ andtrans-[RuCl₄(indazole)₂]⁻. Clarke et al have reviewed the anticancer,and in particular the antimetastatic, activity of ruthenium complexes:Chem. Rev., 1999, 99, 2511-2533. Also, Sava has reviewed theantimetastatic activity in “Metal Compounds in Cancer Therapy” Ed by S PFricker, Chapman and Hall, London 1994, p. 65-91.

Dale et al, Anti-Cancer Drug Design, (1992), 7, 3-14, describes ametronidazole complex of ruthenium(II) ie,[(η⁶-C₆H₆)RuCl₂(metronidazole)] and its effect on DNA and on E. coligrowth rates. Metronidazole sensitises hypoxic tumour cells to radiationand appears to be an essential element of the complexes of Dale et al.There is no indication in Dale et al that the complexes would be at alleffective in the absence of the metronidazole ligand.

Krämer et al, Chem Eur J., 1996, 2, No. 12, p. 1518-1526 discloses halfsandwich complexes of ruthenium with amino esters.

Bennett et al, Canadian Journal of Chemistry, (2001), 79, 655-669discloses certain ruthenium(II) complexes with acetylacetonate ligands.

Oro et al, J Chem Soc, Dalton Trans, (1990), 1463 describesruthenium(II) complexes containing η⁶-p-cymene and acetylacetonateligands.

Our copending application GB 0215526.5 describes ruthenium(II) compoundcontaining a bidentate ligand bearing an overall negative charge.

Chen et al, J. Am. Chem. Soc., volume 124, no 12, 3064, (2002),describes the mechanism of binding of ruthenium complexes to guaninebases. The binding model requires NH bonds from a diamino ligand to bepresent in the complex for hydrogen bonding to the guanine base.Similarly, Morris et al, J. Med. Chem., volume 44, 3616-3621, (2001),describes the selectivity of ruthenium(II) complexes for binding toguanine bases.

WO 01/30790 discloses ruthenium(II) compounds and their use asanticancer agents.

WO 02/02572 also discloses ruthenium(II) compounds that have activityagainst cancer cell lines. Complexes are disclosed containing abidentate ligand which is a neutral diamine ligand.

Garcia et al, Journal of Organometallic Chemistry, 467 (1994), 119-126discloses the preparation of [(η⁶-arene)Ru(o-phenylenediamine)Cl]PF₆wherein arene is benzene or p-cymene.

There exists a need for novel anti-cancer compounds which can be used asalternatives to the compounds which are currently available.

In particular, there exists a need for compounds which can have adifferent profile of activity against different types of tumour cellsand/or which can exhibit activity against cells that are resistant toother anti-cancer agents (such as adriamycin).

The present invention provides a novel class of ruthenium(II) complexeshaving anti-tumour activity.

According to the present invention, there is provided a ruthenium(II)compound of formula (I):

wherein: R¹, R², R³, R⁴, R⁵ and R⁶ independently represent H,(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, hydroxy(C₁-C₆)alkyl,amino(C₁-C₆)alkyl, halo, hydroxyl, CO₂R⁷, CONR⁸R⁹, COR¹⁰, SO₃H,SO₂NR¹¹R¹², aryloxy, (C₁-C₆)alkoxy, (C₁-C₆)alkylthio, —N═N—R¹³, NR¹⁴R¹⁵,aryl or aralkyl, which latter two groups are optionally substituted onthe aromatic ring by one or more groups independently selected from(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, hydroxy(C₁-C₆)alkyl,amino(C₁-C₆)alkyl, aryl, aralkyl, halo, hydroxyl, CO₂R^(7a),CONR^(8a)R^(9a), COR^(10a), SO₃G, SO₂NR^(11a)R^(12a), aryloxy,(C₁-C₆)alkoxy, (C₁-C₆)alkylthio, —N═N—R^(13a), NR^(14a)R^(15a), or R¹and R² together with the ring to which they are bound represent asaturated or unsaturated carbocyclic or heterocyclic group containing upto three 3- to 8-membered carbocyclic or heterocyclic rings, whereineach carbocyclic or heterocyclic ring may be fused to one or more othercarbocyclic or heterocyclic rings, and wherein each of the rings may beoptionally substituted by one or more groups independently selected from(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, hydroxy(C₁-C₆)alkyl,amino(C₁-C₆)alkyl, aryl, aralkyl, halo, hydroxyl, CO₂R^(7b),CONR_(8b)R^(9b), COR^(10b), SO₃G′, SO₂NR^(11b)R^(12b), aryloxy,(C₁-C₆)alkylthio, —N═N—R^(13b), NR^(14b)R^(15b) or (C₁-C₆)alkoxy;one or more of R¹ to R⁶ optionally being covalently bonded via acarbon-carbon, carbon-nitrogen or carbon-oxygen bond to another R¹ to R⁶group on another compound of formula (I);R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R^(7a), R^(8a), R^(9a),R^(10a), R^(11a), R^(12a), R^(13a), R^(14a), R^(15a), R^(7b), R^(8b),R^(9b), R^(10b), R^(11b), R^(12b), R^(13b), R^(14b) and R^(15b) areindependently selected from H, (C₁-C₆)alkyl, aryl or aralkyl;X is a neutral or negatively charged O-, N- or S-donor ligand or halo;G and G′ are independently selected from alkali metals, aryl, aralkyland (C₁-C₆) alkyl;Y is NR¹⁶R¹⁷ and Y′ is NR¹⁸R¹⁹, wherein R¹⁶, R¹⁷, R¹⁸ and R¹⁹ areindependently selected from H, (C₁-C₆)alkyl, aryl or aralkyl;L is 1,2-arylene, 1,2-(C₅-C₈)cycloalkylene or (C₂-C₆)alkylene, providedthat when L is (C₂-C₆)alkylene, one of R¹⁶ and R¹⁷ is covalently bondedto one of R¹⁸ and R¹⁹ such that they form with L a ring containing Y andY′, said 1,2-arylene, 1,2-(C₅-C₈)cycloalkylene and (C₂-C₆)alkylenegroups being optionally fused with one or more saturated or unsaturatedcarbocyclic or heterocyclic groups containing up to three 3- to8-membered carbocyclic or heterocyclic rings, wherein each carbocyclicor heterocyclic ring may be fused to one or more other carbocyclic orheterocyclic rings, said 1,2-arylene, 1,2-(C₅-C₈)cycloalkylene and(C₂-C₆)alkylene groups and/or the groups to which they are fused beingoptionally substituted with one or more groups independently selectedfrom (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, hydroxy(C₁-C₆)alkyl,amino(C₁-C₆)alkyl, halo, hydroxyl, nitro, CO₂R^(7′), CONR^(8′)R^(9′),COR^(10′), SO₃H, SO₂N R^(11′)R^(12′), aryloxy, (C₁-C₆)alkoxy,(C₁-C₆)alkylthio, —N═N—R^(13′), NR^(14′)R^(15′), aryl or aralkyl, andhaving one or more CH₂ groups optionally replaced by C═O groups, whereinR^(7′), R^(8′), R^(9′), R^(10′), R^(11′), R^(12′), R^(13′), R^(14′) andR^(15′) are independently selected from H, (C₁-C₆)alkyl, aryl oraralkyl;m is −2, −1, 0, +1 or +2 and the compound comprises a counterion when mis not 0;the compound of formula (I) optionally being in the form of a dimer inwhich two L groups are linked either directly or through a groupcomprising one or more of (C₁-C₆)alkylene, (C₁-C₆)alkenylene, arylene,aralkylene, alkarylene, Se, Se—Se, S—S, N═N and C═O or in which L bearstwo Y groups and two Y′ groups;provided that when R², R³, R⁵ and R⁶ are all H, X is chloro, Y and Y′are both NH₂ and L is 1,2-phenylene, R¹ is not CH₃ when R⁴ is CH(CH₃)₂and R¹ and R⁴ are not both H.

The compounds of the invention may be in the form of pharmaceuticallyacceptable salts, solvates and/or prodrugs. Prodrugs are variants of thecompounds of the invention which can be converted to compounds offormula (I) in vivo.

The compounds of formula (I) may have one or more chiral centres. Whenthe compounds of formula (I) have one or more chiral centres, they maybe in the form of one enantiomer, may be enriched in one enantiomer ormay be a racemic mixture.

The term “alkyl” as used herein includes C₁ to C₆ alkyl groups which maybe branched or unbranched and may be open chain or, when they are C₃ toC₆ groups, cyclic. Unbranched open chain alkyl groups include, forexample, methyl, ethyl, propyl, butyl, pentyl and hexyl. Branched openchain alkyl groups include, for example, 2-propyl, 2-butyl and2-(2-methyl)propyl. Cyclic groups include cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl. The alkyl groups in the compounds of theinvention may optionally be substituted. Substituents include one ormore further unsubstituted alkyl groups and/or one or more furthersubstituents, such as, for example, cyano, nitro, —CO₂(C₁-C₆)alkyl,halo, thiol (SH), thioether (eg, S—(C₁-C₆)alkyl) and sulfonate. The term“alkoxy” means —O-alkyl. The term “alkylthio” means —S-alkyl.

The terms “hydroxy(C₁-C₆)alkyl” and “amino(C₁-C₆)alkyl” refer to alkylgroups, as defined above, substituted with one or more hydroxyl (OH) oramino (NH₂) groups, respectively.

The terms “alkenyl” and “alkynyl” are defined similarly to the term“alkyl” but refer to groups that contain from 2 to 6 carbon atoms andinclude one or more carbon-carbon double bonds or one or morecarbon-carbon triple bonds, respectively. Alkenyl and alkynyl groups maybe optionally substituted in the same way as alkyl groups. Examples ofalkenyl groups are ethenyl, 1-propenyl, 2-propenyl, 1-butenyl,2-butenyl, 1,4-butadienyl, cyclohexenyl and cyclohexadienyl.

The term “alkylene” is defined similarly to the definition of the term“alkyl” but includes C₂ to C₆ groups and represents a divalent specieswith radicals separated by two or more (eg, from two to six) carbonatoms linked in a chain. Preferably, the alkylene groups are straightchain groups. Examples of alkylene groups are 1,2-ethylene and1,3-propylene. The terms “alkenylene” and “alkynylene” are definedsimilarly and refer to divalent radicals containing one or morecarbon-carbon double bonds or one or more carbon-carbon triple bonds,respectively.

The term “aryl” as used herein includes aromatic carbocyclic rings suchas phenyl, naphthyl and anthracenyl and heterocyclic rings such aspyridyl, imidazolyl, pyrrolyl and furanyl. Aryl groups may optionally besubstituted with one or more substituents including, for example,(C₁-C₆)alkyl, cyano, nitro, hydroxyl, halo(C₁-C₆)alkyl,—CO₂(C₁-C₆)alkyl, halo, thiol (SH), thioether (eg, S—(C₁-C₆)alkyl) andsulfonate (SO₃H). The term “aryloxy” means —O-aryl.

The term “heterocyclic ring” refers to a 3-, 4-, 5-, 6-, -7, or 8-(preferably 5-, 6- or 7-) membered saturated or unsaturated ring, whichmay be aromatic or non-aromatic, containing from one to threeheteroatoms independently selected from N, O and S, eg, indole.

The term “arylene” refers to a divalent radical comprising an aromaticcarbocyclic or heterocyclic ring in which the radicals are present atdifferent positions on the ring. An example of an arylene group is1,2-phenylene.

The term “aralkyl” means alkyl substituted with aryl eg, benzyl. Theterm “alkaryl” means aryl substituted with alkyl eg, methylphenyl.

The term “aralkylene” refers to a divalent radical that can be derivedfrom an aralkyl group eg, 1-methylene-4-phenyl. Each of the two radicalsmay be present on the aryl ring or on the alkyl group or one of theradicals may be present on the alkyl group and the other radical presenton the aryl ring. The term “alkarylene” is defined similarly.

The term ferrocenylene refers to a diradical derived from ferrocene(FeCp₂). Each radical may be present on the same ring or on differentrings.

The term “halo” means a halogen radical selected from fluoro, chloro,bromo and iodo. Chloro is particularly preferred. When X is halo informula (I), it will be appreciated that X may be thought of as havingat least some of the character of a negatively charged ion rather thanbeing covalently bonded to the ruthenium atom. Indeed, all ligands X mayhave some ionic as well as some covalent character.

The term “haloalkyl” means alkyl substituted with one or more halogroups eg, trifluoromethyl.

In the compounds of the invention, R¹ and R² together with the ring towhich they are bound in compounds of formula (I) may represent an ortho-or peri-fused carbocyclic or heterocyclic ring system. The carbocyclicand heterocyclic ring systems can be saturated or unsaturated. When thecarbocyclic or heterocyclic ring systems are unsaturated, they can bearomatic or non-aromatic. R¹ and R² together with the ring to which theyare bound may, for example, represent a wholly carbocyclic fused ringsystem such as a ring system containing 2 or 3 fused carbocyclic ringseg, optionally substituted, optionally hydrogenated naphthalene oranthracene. Thus, R¹ and R² together with the ring to which they arebound in compounds of formula (I) may represent a fused bicyclic ringsuch as indan, a fused tricyclic ring such as anthracene or a mono, di,tri, tetra or higher hydrogenated derivative of anthracene. For example,R¹ and R² together with the ring to which they are bound in formula (I)may represent 1,2,3,4-tetrahydronaphthalene, anthracene,1,4-dihydroanthracene or 1,4,9,10-tetrabydroanthracene.

Preferably, R¹, R², R³, R⁴, R⁵ and R⁶ are independently selected from H,(C₁-C₆)alkyl and phenyl or R¹ and R² together with the ring to whichthey are bound represent indan, anthracene or a hydrogenated derivativeof anthracene, said phenyl, indan and anthracene or a hydrogenatedderivative of anthracene being optionally substituted by one or moregroups independently selected from (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, hydroxy(C₁-C₆)alkyl, amino(C₁-C₆)alkyl, phenyl, benzyl,halo, hydroxyl, carboxyl, CO₂(C₁-C₆)alkyl, CONH₂, COH, CO(C₁-C₆)alkyl,SO₃H, SO₂NH₂, phenoxy, (C₁-C₆)alkylthio, NH₂ or (C₁-C₆)alkoxy. Mostpreferably, one of R¹, R², R³, R⁴, R⁵ and R⁶ is phenyl and the othergroups are all H, or one or two of R¹, R², R³, R⁴, R⁵ and R⁶ is or are(C₁-C₆)alkyl and the other groups are H, or R¹ and R² together with thering to which they are bound represent anthracene or a hydrogenatedderivative of anthracene.

In another embodiment of the invention, one or more of R¹ to R⁶ is orare optionally covalently bonded via a carbon-carbon, carbon-nitrogen orcarbon-oxygen bond to another R¹ to R⁶ group on another compound offormula (I). Thus, the compounds of the invention may be multinuclearcomplexes in which two or more compounds of formula (I) are linkedtogether. Examples of dinuclear complexes include compounds in which theC₆(R¹R²R³R⁴R⁵R⁶) group is a group of formulaC₆(R²R³R⁴R⁵R⁶)—R¹—C₆(R²R³R⁴R⁵R⁶), wherein R¹ is (C₁-C₆)alkyleneoptionally comprising one or more groups of formula —O—, NR¹⁴ and(NR¹⁴R¹⁵)⁺, wherein R¹⁴ and R¹⁵ are as defined above. Also, two or moreother groups on the aromatic rings can be linked such that a tricyclicring is formed, for example in the form of a dibenzo crown ether.Trinuclear complexes include, for example, those compounds in which theC₆(R¹R²R³R⁴R⁵R⁶) group is a group of formula X′(—R¹—(C₆(R²R³R⁴R⁵R⁶))₃,wherein X′ is CR¹⁴, N or (NR¹⁴)⁺ and R¹⁴ is as defined above. Similarly,examples of tetranuclear complexes are those compounds in which theC₆(R¹R²R³R⁴R⁵R⁶) group is a group of formula C(—R¹—(C₆(R²R³R⁴R⁵R⁶))₄.

Compounds of the invention may be charged (either positively ornegatively) or uncharged. In formula (I), it is preferred that m is +1.When m is not equal to zero, the compounds of formula (I) comprise acounterion. Suitable counterions include non-nucleophilic ions such as,for example, PF₆ ⁻ and BF₄ ⁻.

In compounds of formula (I), X is a neutral or negatively charged O-, N-or S-donor ligand or halo. Suitable ligands include, for example, H₂O,di((C₁-C₆)alkyl)S(O), (C₁-C₆)alkylCO₂ ⁻ or di((C₁-C₆)alkyl)C═O. Otherligands include, for example, N-donor nitrile ligands (eg, compounds offormula (C₁-C₆)alkylCN) and N-donor pyridine ligands, optionallysubstituted at one or more of the carbon rings of the pyridine ring eg,by (C₁-C₆)alkyl or halo. Other suitable ligands are (C₁-C₆)alkyl primaryamines such as methylamine and ethylamine. Preferably, X is halo orCH₃CN, most preferably, X is chloro.

Y-L-Y′ is a bidentate ligand. Preferably, Y-L-Y′ is selected fromligands of formulae (II) to (IV):

wherein: n is 1, 2 or 3, each pair of groups R^(8d) and R^(9d) are thesame or different when n is 2 or 3; andR^(1c) to R^(9c), R^(1d) to R^(9d) and R^(1e) to R^(4e), areindependently selected from H, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, hydroxy(C₁-C₆)alkyl, amino(C₁-C₆)alkyl, halo, hydroxy,CO₂R^(7′), CONR^(8′)R^(9′), COR^(10′), SO₃H, SO₂N R^(11′)R^(12′),aryloxy, (C₁-C₆)alkoxy, (C₁-C₆)alkylthio, —N═N—R^(13′), NR^(14′)R^(15′),aryl or aralkyl, and one or more of pairs of groups R^(1c) to R^(9c),R^(1d) to R^(9d) and R^(1c) to R^(4c) that are bonded to the same oradjacent carbon atoms (i.e., carbon atoms that are directly bonded toeach other) are optionally covalently bonded to each other to form asaturated or unsaturated carbocyclic or heterocyclic group (thecarbocyclic and heterocyclic ring systems can be saturated orunsaturated, and when the carbocyclic or heterocyclic ring systems areunsaturated and bonded to adjacent carbon atoms, they can be aromatic ornon-aromatic), and Y-L-Y′ is optionally in the form of a dimer in whichtwo compounds of formula (II), two compounds of formula (III) or twocompounds of formula (IV) are directly covalently bonded to each other.

The two nitrogen atoms in formulae (II) to (IV) coordinate to theruthenium atom in formula (1).

It is also preferred that R^(1c) to R^(9c), R^(1d) to R^(9d) and R^(1e)to R^(4e), are independently selected from H, (C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl, amino(C₁-C₆)alkyl, halo, hydroxyl, CO₂(C₁-C₆)alkyland (C₁-C₆)alkoxy.

It is particularly preferred that Y-L-Y′ is a ligand of formula (V)

wherein R^(1f), R^(2f), R^(3f) and R^(4f) are independently selectedfrom H, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,hydroxy(C₁-C₆)alkyl, amino(C₁-C₆)alkyl, halo, hydroxyl, CO₂R^(7′),CONR^(8′)R^(9′), CORN^(10′), SO₃H, SO₂NR^(11′)R^(12′), aryloxy,(C₁-C₆)alkoxy, (C₁-C₆)alkylthio, —N═N—R^(13′) and NR^(14′)R^(15′). Morepreferably, R^(1f), R^(2f), R^(3f) and R^(4f) are independently selectedfrom H, (C₁-C₆)alkyl and hydroxyl.

For example, it is preferred that in Y-L-Y′ L is 1,2-phenylene,1,2-cyclohexylene or a (C₄-C₆)heterocycle containing two nitrogen atoms(e.g., piperazinyl or homopiperazinyl), optionally substituted with withone or more groups independently selected from (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, hydroxy(C₁-C₆)alkyl, amino(C₁-C₆)alkyl,phenyl, benzyl, halo, hydroxyl, carboxyl, CO₂(C₁-C₆)alkyl, CONH₂, COH,CO(C₁-C₆)alkyl, SO₃H, SO₂NH₂, phenoxy, (C₁-C₆)alkylthio, NH₂ or(C₁-C₆)alkoxy.

More preferably, in Y-L-Y′, R¹⁶, R¹⁷, R¹⁸ and R¹⁹ are all H. Forexample, R¹⁶, R¹⁷, R¹⁸ and R¹⁹ may be H and L is 1,2-phenylene,1,2-cyclohexylene or homopiperazinyl, optionally substituted with one ortwo groups selected from (C₁-C₆)alkyl and hydroxy.

Another group of ligands Y-L-Y′ are those which comprise a fusedcarbocyclic ring system in which one or more of the CH₂ groups of thefused ring system are optionally replaced by C═O groups. Examples ofthis group of ligands are those in which Y-L-Y′ is a ligand of formula(VIA) or (VIB)

wherein R^(1g), R^(2g), R^(3g), R^(4g), R^(5g) and R^(6g) areindependently selected from H, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, hydroxy(C₁-C₆)alkyl, amino(C₁-C₆)alkyl, halo, hydroxyl,CO₂R^(7′), CONR^(8′)R^(9′), COR^(10′), SO₃H, SO₂NR^(11′)R^(12′),aryloxy, (C₁-C₆)alkoxy, (C₁-C₆)alkylthio, —N═N—R^(13′) andNR^(14′)R^(15′). Preferably, all of R^(1g), R^(2g), R^(3g), R^(4g),R^(5g) and R^(6g) are H. It is also preferred that the ligand is offormula (VIA).

The compounds of formula (I) may be in the form of dimers, which mayalso be termed dinuclear complexes—such complexes contain two rutheniumatoms. Dinuclear complexes can be provided by employing a ligand whichcomprises two linked ligands Y-L-Y′ so as to bridge between tworuthenium centres. Preferably such linkage is by way of a directcovalent bond between two L groups, so that the ligand has the formulaYY′L-LYY′.

Compounds of formula (I) and ligands of formula Y-L-Y′ may exist in oneor more tautomeric forms, all of which are covered by the presentinvention.

A particularly preferred group of compounds of formula-(I) are those inwhich: R¹, R², R³, R⁴, R⁵ and R⁶ are independently selected from H,(C₁-C₆)alkyl and phenyl or R¹ and R² together with the ring to whichthey are bound represent indan, anthracene or a hydrogenated derivativeof anthracene, said phenyl, indan and anthracene or a hydrogenatedderivative of anthracene group being optionally substituted with one ormore groups independently selected from (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, hydroxy(C₁-C₆)alkyl, amino(C₁-C₆)alkyl, phenyl, benzyl,halo, hydroxyl, carboxyl, CO₂(C₁-C₆)alkyl, CONH₂, COH, CO(C₁-C₆)alkyl,SO₃H, SO₂NH₂, phenoxy, (C₁-C₆)alkylthio, NH₂ or (C₁-C₆)alkoxy;

X is chloro;

m is +1;

R¹⁶, R¹⁷, R¹⁸ and R¹⁹ are all H; and

L is 1,2-phenylene, 1,2-cyclohexylene or a (C₄-C₆)heterocycle containingtwo nitrogen atoms (e.g., piperazinyl or homopiperazinyl), optionallysubstituted with with one or more groups independently selected from(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, hydroxy(C₁-C₆)alkyl,amino(C₁-C₆)alkyl, phenyl, benzyl, halo, hydroxyl, carboxyl,CO₂(C₁-C₆)alkyl, CONH₂, COH, CO(C₁-C₆)alkyl, SO₃H, SO₂NH₂, phenoxy,(C₁-C₆)alkylthio, NH₂ or (C₁-C₆)alkoxy.

A further preferred group of compounds of formula (I) is that in which:

one of R¹, R², R³, R⁴, R⁵ and R⁶ is phenyl and the other groups are allH, or one or two of R¹, R², R³, R⁴, R⁵ and R⁶ is or are (C₁-C₆)alkyl andthe other groups are H, or R¹ and R² together with the ring to whichthey are bound represent indan, anthracene or a hydrogenated derivativeof anthracene;

X is chloro;

m is +1;

R¹⁶, R¹⁷, R¹⁸ and R¹⁹ are all H; and

L is 1,2-phenylene, 1,2-cyclohexylene or homopiperazinyl, optionallysubstituted with one or two groups selected from (C₁-C₆)alkyl andhydroxy.

The compounds of the invention comprising the complex[(η⁶-biphenyl)Ru(o-phenylenediamine)Cl]⁺, particularly as its salt withthe counterion PF₆ ⁻, is particularly preferred.

The compounds of the invention have been found to exhibit cytotoxicactivity against cancer cell lines and can therefore be expected to showanticancer activity.

In another embodiment, therefore, the present invention provides acompound of formula (I) as defined above without the proviso for use inmedicine. The invention also contemplates the provision of a compound offormula (I) as defined above without the proviso for use in thetreatment and/or prevention of cancer and the use of a compound offormula (I) as defined above without the provisos in the treatmentand/or prevention of cancer.

Also provided by the invention is the use of a compound of formula (I)as defined above without the proviso in the manufacture of a medicamentfor the treatment and/or prevention of cancer.

Further provided by the invention is a pharmaceutical compositioncomprising a compound of formula (I) as defined above without theproviso together with one or more pharmaceutically acceptableexcipients.

Yet another aspect of the invention is a method of treating and/orpreventing cancer which comprises administering to a subject atherapeutically effective amount of a compound of formula (I) as definedabove without the proviso or a composition of the invention.

The compounds of the invention may be used directly against a tumour.Alternatively or additionally, the compounds may be used to prevent orinhibit metastasis and/or to kill secondary tumours. It will beunderstood that the prevention or inhibition of metastasis isencompassed by the term “preventing cancer”, as used herein.

The term “tumour” is to be understood as referring to all forms ofneoplastic cell growth, including tumours of the lung, liver, bloodcells, skin, pancreas, stomach, colon, prostate, uterus, breast, lymphglands and bladder. Ovarian tumours may especially suitable fortreatment according to the invention.

Compounds of the invention may be effective in treating and/orpreventing tumours caused by cells that are resistant to other cytotoxicdrugs, such as cis-platin, for example.

Certain compounds of the invention have the surprising advantage thatthey exhibit improved non-cross resistance with other anti-cancer agentssuch as cis-platin and adriamycin whilst still possessing good activityagainst non-resistant tumour cells. It is clearly highly desirable to beable to kill tumour cells that have developed resistance to otheranti-cancer agents.

The compounds of the invention may be administered by a number of routesincluding, for example, orally, parenterally (eg, by injectionintramuscularly, intravenously or subcutaneously), topically, nasally orvia slow releasing microcarriers. Thus, suitable excipients for use inthe pharmaceutical compositions of the invention include saline, sterilewater, creams, ointments, solutions, gels, pastes, emulsions, lotions,oils, solid carriers and aerosols.

The compositions of the invention may be formulated in unit or sub-unitdosage form including, for example, tablets, capsules and lozenges andcontainers containing the composition in a form suitable for parenteraladministration. Preferably, the compositions are in a form that issuitable for injection.

The specific dosage level of the compounds and compositions of theinvention will depend upon a number of factors, including the biologicalactivity of the specific compound used and the age, body weight and sexof the subject. It will be appreciated that the subject may be a humanor a mammalian animal.

The compounds and compositions of the invention can be administeredalone or in combination with other compounds. The other compounds mayhave a biological activity which complements the activity of thecompounds of the invention eg, by enhancing its effect in killingtumours or by reducing any side-effects associated with the compounds ofthe invention.

In another embodiment, the present invention provides a process forpreparing the compound of formula (1) which comprises the reaction of acompound of formula [(η⁶-C₆(R¹)(R²)(R³)(R⁴)(R⁵)(R⁶))RuX₂], optionally inthe form of a dimer, with Y-L-Y′, in a suitable solvent for thereaction, wherein R¹, R², R³, R⁴, R⁵, R⁶, X, Y, Y′ and L are as definedfor formula (I) above. Preferably, the process comprises the reaction ofa compound of formula [(η⁶-C₆(R¹)(R²)(R³)(R⁴)(R⁵)(R⁶))RuX₂], optionallyin the form of a dimer, with Y-L-Y′ at a temperature of from 0° C. to100° C. (eg, 10° C. to 80° C.) in a polar solvent (such as a(C₁-C₄)alkanol, di(C₁-C₆)alkyl ketone (eg, acetone) or water or mixturesthereof). The compound of formula (I) can be separated from the reactionmixture, for example by crystallisation from the reaction mixturefollowing the addition of a counterion for the compound of formula (I)(e.g., PF₆ ⁻) in the form of a salt that is soluble in the reactionmixture e.g., NH₄ ⁺PF₆ ⁻. The compound is optionally purified (eg, byrecrystallisation from a suitable solvent or mixture of two or moredifferent solvents).

Suitable compounds of formula [(η⁶-C₆(R¹)(R²)(R³)(R⁴)(R⁵)(R⁶))RuX₂] foruse as starting materials (starting ruthenium complexes) in the processof the invention can be produced as described in WO 01/30790 and WO02/02572. Compounds of formula Y-L-Y′ are either commercially availableor can be synthesised by routes well known to those skilled in the art.

The invention will now be described with reference to the followingnon-limiting examples.

EXAMPLES

Starting Materials

[Ru(η-p-cymene)(CH₃CN)₂Cl]PF₆ was prepared as follows.[Ru(η⁶-p-cymene)Cl₂]₂ (0.50 g, 0.74 mmol) and NH₄PF₆ (0.256 g, 1.6 mmol)was placed in CH₃CN (20 ml) and stirred for 18 hours at ambienttemperature. The precipitate was removed by filtration and the solventremoved on the rotary evaporator to give an orange/red oil. Ether wasadded and trituration gave a yellowish orange solid.

Yield 0.635 g (91%).

The above complex was used as a starting material for Example 6.

Example 1 [(η⁶-Biphenyl)Ru(o-phenylenediamine)Cl]PF₆

The dimer [Ru(Biphenyl)Cl₂]₂ (0.220 g, 0.35 mmol) was suspended inMeOH/H₂O (50 ml/10 ml) and heated under reflux for one hour and cooledto ambient temperature. Diaminobenzene (0.065 g, 0.60 mmol) in MeOH (5ml) was then added dropwise and the reaction mixture further heatedunder reflux for 15 min and filtered. To the filtrate NH₄PF₆ (0.122 g,0.75 mmol) was added and the volume of the filtrate reduced on therotary evaporator to about 20 ml and kept in the freezer overnight togive a brownish microcrystalline solid. The product was collected byfiltration, washed with MeOH and ether and dried in air. It wasrecrystallised from MeOH.

Yield (0.180 g, 54%)

¹H δ (DMSOd₆): 8.49 (d, NH, 2H), 7.81 (m, 2H), 7.47 (m, 3H), 7.18-7.15(m, 4H), 6.46 (d, NH, 2H), 6.28 (m, 2H), 6.00 (m, 1H), 5.86 (m, 2H).

Example 2 {[(η⁶-Biphenyl)Ru(diaminobenzidine)Cl]PF₆}₂

The dimer [Ru(Biphenyl)Cl₂]₂ (0.365 g, 0.55 mmol) was suspended in MeOH(50 ml) and heated under reflux for one hour and cooled to ambienttemperature. Diaminobenzidine (0.065 g, 0.107 mmol) in MeOH (10 ml) wasthen added dropwise and the reaction mixure further heated under refluxfor 20 min and filtered. To the filtrate NH₄PF₆ (0.401 g, 2.45 mmol) wasadded and the volume of the filtrate reduced on the rotary evaporator toabout 20 ml and kept in the freezer overnight to give a brownishmicrocrystalline solid. The product was collected by filtration, washedwith MeOH and ether and dried in air.

Yield (0.435 g, 80%). ¹H δ (DMSOd₆): 8.42 (m, NH, 4H), 7.86 (m, 4H), 7.5(m, 6H), 7.36-7.51 (m, 6H), 6.58 (m, NH, 4H), 6.30 (m, 4H), 6.02 (m,2H), 5.91 (m, 4H).

Example 3 [(η⁶-dihydroanthracene)Ru(o-phenylenediamine)Cl]PF₆

The dimer [Ru(tetrahydroanthracene)Cl₂]₂ (0.140 g, 0.20 mmol) wassuspended in MeOH (40 ml) and water (8 ml) and heated under reflux forone hour and cooled to ambient temperature. 1,2-Diaminobenzene (0.045 g,0.042 mmol) in MeOH (5 ml) was then added dropwise and the reactionmixure further heated under reflux for 20 min and filtered to give a redsolution. To the filtrate NH₄PF₆ (0.100 g, 0.61 mmol) was added and thesolvent was taken off on the rotary evaporator to give a reddish solid.The solid was recrystallised from methanol and was collected byfiltration, washed with MeOH and ether and dried in air.

Yield 81 mg, 35% ¹H δ (DMSOd₆): 8.15 (d, NH, 2H), 7.24-7.13 (m, 8H),6.25 (d, NH, 2H), 5.78-5.73 (m, 4H), 4.11-3.92 (m, 4H).

Example 4 [(η⁶-Biphenyl)Ru(2,3-diaminophenol)Cl]PF₆

The above complex was prepared in the same way as the compound ofExample 2.

Yield 38%

¹H δ (DMSOd₆): 8.30 (d, NH, 1H), 8.04 (d, NH, 1H), 7.82 (m, 2H), 7.49(m, 3H) 6.98 (m, 1H), 6.65 (m, 2H), 6.43 (d, NH, 1H), 6.24 (m, 2H),6.01-5.94 (m, 3H), 5.46 (m, NH, 1H).

Example 5 [(η⁶-indan)Ru(3,4-diaminotoluene)Cl]PF₆

The dimer [Ru(C₉H₁₀)Cl₂]₂, ([Ru(indan)Cl₂]₂) (0.244 g, 0.42 mmol) wasdissolved in MeOH (25 ml) and 3,4-diaminotoluene (0.100 g, 0.84 mmol) inMeOH (5 ml) was added and stirred at ambient temperature for two hours.It was filtered and to the filtrate NH₄PF₆ (0.205 g, 1.26 mmol) wasadded and the volume of the filtrate reduced on the rotary evaporator toabout 3 ml and kept in the freezer overnight to give a brownishmicrocrystalline solid. The product was collected by filtration, washedwith MeOH and ether and dried in air. It was recrystallised from MeOH.

Yield 79%

¹H δ (DMSOd₆): 8.04 (m, NH, 2H), 7.08 (m, 1H), 6.98 (m, 2H), 6.21 (m,NH, 2H), 5.73 (m, 2H), 5.63 (m, 2H), 2.25 (s, 3H), 2.74-2.68 (m, 4H),2.09-1.97 (m, 2H).

Example 6 [(η⁶-p-cymene)Ru(o-phenylenediamine)Cl]PF₆

[Ru(η-p-cymene)(CH₃CN)₂Cl]PF₆ (0.12 g 0.25 mmol) was dissolved in CH₃CN(20 ml) to give a yellowish solution. To this 1,2 phenylenediamine(0.151 g, 1.40 mmol) was added and the reaction mixture stirred atambient temperature for 18 hours to give a deep red solution. Thesolvent was removed on the rotary evaporator to give a brownish/red oilysolid. This was washed many times with ether and triturated to give areddish powder. Yield 47%.

¹H δ (DMSOd₆): 8.58 (d, NH, 2H), 7.20-7.23 (m, 4H), 6.21 (d, NH, 2H),5.85 (d, 2H), 5.65 (d, 2H), 3.06 (s, 1H), 2.26 (s, 3H), 1.23 (d, 6H).

Example 7[(η⁶-1,2,3,4-tetrahydronaphthalene)Ru(1,2-diamino-4-nitrobenzene)Cl]PF₆

To [Ru(C₁₀H₁₂)Cl₂]₂ (0.154 g, 0.253 mM) in MeOH (30 ml), 1,2diamino-3-nitro benzene (0.078 g, 0.51 mM) suspended in MeOH (5 ml) wasadded and the reaction mixture stirred at ambient temperature for 2.5hours to give a clear dark red solution. The solution was filtered andthe volume of the filtrate was reduced on the rotary evaporator to about7 ml. NH₄PF₆ (0.2 g, 1.2 mM) was added and the flask left at −20° C. fortwo days. Dark/black solid (0.55 g) was collected by filtration.

NMR (DMSOd₆) 1.93 (m, 2H), 2.60(m, 2H), 2.75 (m, 2H), 5.0 (s, NH₂), 5.52(m, 2H), 5.74 (m, 2H), 6.52 (s, 1H), 7.38 (m, 2H).

Example 8 [(η⁶-indan)Ru(1,2-diaminoanthraquinone)Cl]Cl

To [Ru(C₉H₁₀)Cl₂] (0.170 g, 0.3 mM) in MeOH (40 ml),1,2-diaminoanthraquinone 0.143 g, 0.6 mM) was added and the reactionmixture stirred at ambient temperature for 2 h. After this time areddish/violet solid precipitated out of solution. The precipitate wascollected by filtration and dried in air. Yield 0.23 g, 75%.

NMR (DMSOd₆) 1.93 (m, 2H), 2.60 (m, 2H), 2.75 (m, 2H), 5.77 (m, 2H),5.88 (m, 2H), 6.30 (s, 2H, NH₂), 6.70 (d, 1H), 7.47 (d, 1H), 7.80 (m,2H), 7.90 (s, 2H, NH₂), 8.10 (m, 1H), 8.20 (m, 1H).

Example 9[(η⁶-1,2,3,4-tetrahydronaphthalene)Ru(1,2-diaminoanthraquinone)Cl]Cl

The compound of Example 9 was prepared in an analogous way to thecompound of Example 8. Yield (70%). NMR (DMSOd₆) 1.66-1.73(m, 4H),2.42-2.45(m, 2H), 2.74-2.77 (m, 2H), 5.54 (m, 2H), 5.73 (m, 2H), 6.33(s, 2H, NH₂), 6.77 (d, 1H), 7.47 (d, 1H), 7.80 (m, 2H), 7.92 (s, 2H,NH₂), 8.10 (m, 1H), 8.20 (m, 1H).

B. Biological Data

1. Protocol for Testing Ru Compounds

The human ovarian cells were added at a density of 1×10⁴ cells per wellto 24-well tissue culture trays (Falcon Plastic, Becton Dickenson,Lincon Park, N.J., USA) and allowed to grow for 72 h before addition ofthe Ru(II) arene complexes. Stock solutions of the ruthenium compoundswere made up fresh in deionised water and sonicated to ensure completedissolution. These stock solutions were diluted with media to give finalconcentrations ranging between 0.1 and 100 μM. All compounds wereevaluated at each concentration in duplicate wells, and complete assayswere repeated a minimum of three times. Cisplatin or carboplatin wasemployed as a positive and comparative control in each experiment. After24-hours exposure the drug-containing medium was removed, the cellswashed with phosphate buffered saline (PBS) and fresh medium was added.Cell number was assessed after a further 72 h growth using a Coultercounter (Coulter Electronics Ltd, Luton, UK) and the IC₅₀ values(concentration of drug causing 50% growth inhibition) calculated bylinear regression analysis comparing the inhibitory effects of the drugsagainst the growth of untreated cells.

The cell lines and methods used are also described in Aird et al, Br. J.Cancer, (2002), 86, 1652-1657.

2. Results

Using the above protocol, a number of compounds of the invention weretested on A2780 ovarian cancer cell line, on an A2780 ovarian cancercell line resistant to cis-platin (A2780^(CIS)), and on an A2780 ovariancancer cell line resistant to adriamycin (A2780^(AD)). Some of thecompounds were tested on an A549 cell line. The results are shown inTable 1: Table 1 is a summary of cytotoxicity data for different celltypes A2780^(CIS) A2780^(AD) Schematic A2780 Fold fold Example structureIC₅₀ (μM) resistance resistance EX 1

5 1 0.8 EX 2

52 EX 3

7 5 2 EX 4

32 EX 5

4 EX 6

11 1 0.6 Schematic A2780 A549 Example Structure IC₅₀ (μM) IC₅₀ (μM)Example 7

59 148 Example 8

15 48 Example 9

37 61

Data were obtained showing cytotoxicity for the analogues of thecompounds of Examples 1, 3 and 6 in which the 1,2-diaminobenzene ligandis replaced by a 1,2-diaminoethane ligand (comparative Examples 1, 2 and3, respectively) in an otherwise identical molecule. The results are asfollows: A2780^(CIS) A2780 Fold A2780^(AD) Example IC₅₀(μM) resistancefold resistance EX 1 5 1 0.8 Comparative 5 1 45 Example 1 EX 3 7 5 2Comparative 2 0.5 >100 Example 2 EX 6 11 1 0.6 Comparative 10 0.6 10Example 3

1. Ruthenium(II) compound of formula (I):

wherein: R¹, R², R³, R⁴, R⁵ and R⁶ independently represent H,(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, hydroxy(C₁-C₆)alkyl,amino(C₁-C₆)alkyl, halo, hydroxyl, CO₂R⁷, CONR⁸R⁹, COR¹⁰, SO₃H,SO₂NR¹¹R¹², aryloxy, (C₁-C₆)alkoxy, (C₁-C₆)alkylthio, —N═N—R¹³, NR¹⁴R¹⁵,aryl or aralkyl, which latter two groups are optionally substituted onthe aromatic ring by one or more groups independently selected from(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, hydroxy(C₁-C₆)alkyl,amino(C₁-C₆)alkyl, aryl, aralkyl, halo, hydroxyl, CO₂R^(7a),CONR^(8a)R^(9a), COR^(10a), SO₃G, SO₂NR^(11a)R^(12a), aryloxy,(C₁-C₆)alkoxy, (C₁-C₆)alkylthio, —N═N—R^(13a), NR^(14a)R^(15a), or R¹and R² together with the ring to which they are bound represent asaturated or unsaturated carbocyclic or heterocyclic group containing upto three 3- to 8-membered carbocyclic or heterocyclic rings, whereineach carbocyclic or heterocyclic ring may be fused to one or more othercarbocyclic or heterocyclic rings, and wherein each of the rings may beoptionally substituted by one or more groups independently selected from(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, hydroxy(C₁-C₆)alkyl,amino(C₁-C₆)alkyl, aryl, aralkyl, halo, hydroxyl, CO₂R^(7b),CONR^(8b)R^(9b), SO₃G′, SO₂NR^(11b)R^(12b), aryloxy, (C₁-C₆)alkylthio,—N═N—R^(13b), NR^(14b)R^(15b) or (C₁-C₆)alkoxy; one or more of R¹ to R⁶optionally being covalently bonded via a carbon-carbon, carbon-nitrogenor carbon-oxygen bond to another R¹ to R⁶ group on another compound offormula (I); R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R^(7a)R^(8a),R^(9a)R^(10a), R^(11a), R^(12a), R^(13a), R^(14a), R^(15a), R^(7b),R^(8b), R^(9b), R^(10b), R^(11b), R^(12b), R^(13b), R^(14b) and R^(15b)are independently selected from H, (C₁-C₆)alkyl, aryl or aralkyl; X is aneutral or negatively charged O-, N- or S-donor ligand or halo; G and G′are independently selected from alkali metals, aryl, aralkyl and (C₁-C₆)alkyl; Y is NR¹⁶R¹⁷ and Y′ is NR¹⁸R¹⁹, wherein R¹⁶, R¹⁷, R¹⁸ and R¹⁹ areindependently selected from H, (C₁-C₆)alkyl, aryl or aralkyl; L is1,2-arylene, 1,2-(C₅-C₈)cycloalkylene or (C₂-C₆)alkylene, provided thatwhen L is (C₂-C₆)alkylene, one of R¹⁶ and R¹⁷ is covalently bonded toone of R¹⁸ and R¹⁹ such that they form with L a ring containing Y andY′, said 1,2-arylene, 1,2-(C₅-C₈)cycloalkylene and (C₂-C₆)alkylenegroups being optionally fused with one or more saturated or unsaturatedcarbocyclic or heterocyclic groups containing up to three 3- to8-membered carbocyclic or heterocyclic rings, wherein each carbocyclicor heterocyclic ring may be fused to one or more other carbocyclic orheterocyclic rings, said 1,2-arylene, 1,2-(C₅-C₈)cycloalkylene and(C₂-C₆)alkylene groups and/or the groups to which they are fused beingoptionally substituted with one or more groups independently selectedfrom (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, hydroxy(C₁-C₆)alkyl,amino(C₁-C₆)alkyl, halo, hydroxyl, nitro, CO₂R^(7′), CONR^(8′)R^(9′),COR^(10′), SO₃H, SO₂N R^(11′), R^(12′), aryloxy, (C₁-C₆)alkoxy,(C₁-C₆)alkylthio, —N═N—R^(13′), NR^(14′)R^(15′), aryl or aralkyl, andhaving one or more CH₂ groups optionally replaced by C═O groups, whereinR^(7′), R^(8′), R^(9′), R^(10′), R^(11′), R^(12′), R^(13′), R^(14′) andR^(15′) are independently selected from H, (C₁-C₆)alkyl, aryl oraralkyl; m is −2, −1, 0, +1 or +2 and the compound comprises acounterion when m is not 0; the compound of formula (I) optionally beingin the form of a dimer in which two L groups are linked either directlyor through a group comprising one or more of (C₁-C₆)alkylene,(C₁-C₆)alkenylene, arylene, aralkylene, alkarylene, Se, Se—Se, S—S, N═Nand C═O or in which L bears two Y groups and two Y′ groups; providedthat when R², R³, R⁵ and R⁶ are all H, X is chloro, Y and Y′ are bothNH₂ and L is 1,2-phenylene, R¹ is not CH₃ when R⁴ is CH(CH₃)₂ and R¹ andR⁴ are not both H.
 2. Compound as claimed in claim 1, wherein R¹, R²,R³, R⁴, R⁵ and R⁶ are independently selected from H, (C₁-C₆)alkyl andphenyl or R¹ and R² together with the ring to which they are boundrepresent indan, anthracene or a hydrogenated derivative of anthracene,said phenyl, indan and anthracene or a hydrogenated derivative ofanthracene group being optionally substituted by one or more groupsindependently selected from (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, hydroxy(C₁-C₆)alkyl, amino(C₁-C₆)alkyl, phenyl, benzyl,halo, hydroxyl, carboxyl, CO₂(C₁-C₆)alkyl, CONH₂, COH, CO(C₁-C₆)alkyl,SO₃H, SO₂NH₂, phenoxy, (C₁-C₆)alkylthio, NH₂ or (C₁-C₆)alkoxy. 3.Compound as claimed in claim 1, wherein m is +1.
 4. Compound as claimedin claim 1, wherein X is halo.
 5. Compound as claimed in claim 1,wherein Y-L-Y′ is selected from ligands of formulae (II) to (IV):

wherein: n is 1, 2 or 3, each pair of groups R^(8d) and R^(9d) are thesame or different when n is 2 or 3; and R^(1c) to R^(9c), R^(1d) toR^(9d) and R^(1e) to R^(4e), are independently selected from H,(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, hydroxy(C₁-C₆)alkyl,amino(C₁-C₆)alkyl, halo, hydroxyl, CO₂R^(7′), CONR^(8′)R^(9′),COR^(10′), SO₃H, SO₂N R^(11′)R^(12′), aryloxy, (C₁-C₆)alkoxy,(C₁-C₆)alkylthio, —N═N—R¹³, NR^(14′)R^(15′), aryl or aralkyl, and one ormore of pairs of groups R^(1c) to R^(9c), R^(1d) to R^(9d) and R^(1e) toR^(4e) that are bonded to the same or adjacent carbon atoms areoptionally covalently bonded to each other to form a saturated orunsaturated carbocyclic or heterocyclic group, and Y-L-Y′ is optionallyin the form of a dimer in which two compounds of formula (II), twocompounds of formula (III) or two compounds of formula (IV) are directlycovalently bonded to each other.
 6. Compound as claimed in claim 5,wherein R¹⁶, R¹⁷, R¹⁸ and R¹⁹ are all H.
 7. Compound as claimed in claim5, wherein R^(1c) to R^(9c), R^(1d) to R^(9d) and R^(1e) to R^(4e), areindependently selected from H, (C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl,amino(C₁-C₆)alkyl, halo, hydroxyl, CO₂(C₁-C₆)alkyl and (C₁-C₆)alkoxy. 8.Compound as claimed in claim 5, wherein Y-L-Y′ is a ligand of formula(V)

wherein R^(1f), R^(2f), R^(3f) and R^(4f) are independently selectedfrom H, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,hydroxy(C₁-C₆)alkyl, amino(C₁-C₆)alkyl, halo, hydroxyl, CO₂R^(7′),CONR^(8′)R^(9′), COR^(10′), SO₃H, SO₂NR^(11′)R^(12′), aryloxy,(C₁-C₆)alkoxy, (C₁-C₆)alkylthio, —N═N—R^(13′) and NR^(14′)R^(15′). 9.Compound as claimed in claim 5, wherein Y-L-Y′ is a ligand of formula(VIA) or (VIB)

wherein R^(1g), R^(2g), R^(3g), R^(4g), R^(5g) and R^(6g) areindependently selected from H, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, hydroxy(C₁-C₆)alkyl, amino(C₁-C₆)alkyl, halo, hydroxyl,CO₂R^(7′), CONR^(8′)R^(9′), COR^(10′), SO₃H, SO₂NR^(11′)R^(12′),aryloxy, (C₁-C₆)alkoxy, (C₁-C₆)alkylthio, —N═N—R^(13′) andNR^(14′)R^(15′).
 10. Compound as claimed in claim 8, wherein R^(1f),R^(2f), R^(3f) and R^(4f) are independently selected from H,(C₁-C₆)alkyl and hydroxyl.
 11. Compound as claimed in claim 9, whereinR^(1g), R^(2g), R^(3g), R^(4g), R^(5g) and R^(6g) are all H. 12-13.(canceled)
 14. Pharmaceutical composition comprising a compound offormula (I):

wherein: R¹, R², R³, R⁴, R⁵ and R⁶ independently represent H,(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₁-C₆)alkynyl, hydroxy(C₁-C₆)alkyl,amino(C₁-C₆)alkyl, halo, hydroxyl, CO₂R⁷, CONR⁸R⁹, COR¹⁰, SO₃H,SO₂NR¹¹R¹² aryloxy, (C₁-C₆)alkoxy, (C₁-C₆)alkylthio, —N═N—R¹³, NR¹⁴R¹⁵,aryl or aralkyl, which latter two groups are optionally substituted onthe aromatic ring by one or more groups independently selected from(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, hydroxy(C₁-C₆)alkyl,amino(C₁-C₆)alkyl, aryl, aralkyl, halo, hydroxyl, CO₂R^(7a),CONR^(8a)R^(9a), COR^(10a), SO₃G, SO₂NR^(11a)R^(12a), aryloxy,(C₁-C₆)alkoxy, (C₁-C₆)alkylthio, —N═N—R^(13a), NR^(14a)R^(15a), or R¹and R² together with the ring to which they are bound represent asaturated or unsaturated carbocyclic or heterocyclic group containing upto three 3- to 8-membered carbocyclic or heterocyclic rings, whereineach carbocyclic or heterocyclic ring may be fused to one or more othercarbocyclic or heterocyclic rings, and wherein each of the rings may beoptionally substituted by one or more groups independently selected from(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, hydroxy(C₁-C₆)alkyl,amino(C₁-C₆)alkyl, aryl, aralkyl, halo, hydroxyl, CO₂R^(7b),CONR^(8b)R^(9b), COR^(10b), SO₃G′, SO₂NR^(11b)R^(12b), aryloxy,(C₁-C₆)alkylthio, —N═N—R^(13b), NR^(14b)R^(15b) or (C₁-C₆)alkoxy; one ormore of R¹ to R⁶ optionally being covalently bonded via a carbon-carbon,carbon-nitrogen or carbon-oxygen bond to another R¹ to R⁶ group onanother compound of formula (I: R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴,R¹⁵, R^(7a), R^(8a), R^(9a), R^(10a), R^(11a), R^(12a), R^(13a),R^(14a), R^(15a), R^(7b), R^(8b), R^(9b), R^(10b), R^(11b), R^(12b),R^(13b), R^(14b) and R^(15b) are independently selected from H,(C₁-C₆)alkyl, aryl or aralkyl; X is a neutral or negatively charged O-,N- or S-donor ligand or halo; G and G′ are independently selected fromalkali metals, aryl, aralkyl and (C₁-C₆) alkyl; Y is NR¹⁶R¹⁷ and Y′ isNR¹⁸R¹⁹, wherein R¹⁶, R¹⁷, R¹⁸ and R¹⁹ are independently selected fromH, (C₁-C₆)alkyl, aryl or aralkyl; L is 1,2-arylene,1,2-(C₅-C₈)cycloalkylene or (C₂-C₆)alkylene, provided that when L is(C₂-C₆)alkylene, one of R¹⁶ and R¹⁷ is covalently bonded to one of R¹⁸and R¹⁹ such that they form with L a ring containing Y and Y′, said1,2-arylene, 1,2-(C₅-C₈)cycloalkylene and (C₂-C₆)alkylene groups beingoptionally fused with one or more saturated or unsaturated carbocyclicor heterocyclic groups containing up to three 3- to 8-memberedcarbocyclic or heterocyclic rings, wherein each carbocyclic orheterocyclic ring may be fused to one or more other carbocyclic orheterocyclic rings, said 1,2-arylene, 1,2-(C₅-C₈)cycloalkylene and(C₂-C₆)alkylene groups and/or the groups to which they are fused beingoptionally substituted with one or more groups independently selectedfrom (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, hydroxy(C₁-C₆)alkyl,amino(C₁-C₆)alkyl, halo, hydroxyl, nitro, CO₂R^(7′), CONR^(8′)R^(9′),COR^(10′), SO₃H, SO₂N R^(11′)R^(12′), aryloxy, (C₁-C₆)alkoxy,(C₁-C₆)alkylthio, —N═N—R^(13′), NR^(14′)R^(15′), aryl or aralkyl, andhaving one or more CH₂ groups optionally replaced by C═O groups, whereinR^(7′), R^(8′), R^(9′), R^(10′), R^(11′), R^(12′), R^(13′), R^(14′) andR^(15′) are independently selected from H, (C₁-C₆)alkyl, aryl oraralkyl; m is −2, −1, 0, +1 or +2 and the compound comprises acounterion when m is not 0; the compound of formula (I) optionally beingin the form of a dimer in which two L groups are linked either directlyor through a group comprising one or more of (C₁-C₆)alkylene,(C₁-C₆)alkenylene, arylene, aralkylene, alkarylene, Se, Se—Se, S—S, N═Nand C═O or in which L bears two Y groups and two Y′ groups, togetherwith one or more pharmaceutically acceptable excipients.
 15. A method oftreating and/or preventing cancer which comprises administering to asubject a therapeutically effective amount of a compound of formula (I):

wherein: R¹, R², R³, R⁴, R⁵ and R⁶ independently represent H,(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₁-C₆)alkynyl, hydroxy(C₁-C₆)alkyl,amino(C₁-C₆)alkyl, halo, hydroxyl, CO₂R⁷, CONR⁸R⁹, COR¹⁰, SO₃H,SO₂NR¹¹R¹², aryloxy, (C₁-C₆)alkoxy, (C₁-C₆)alkylthio, —N═N—R¹³, NR¹⁴R¹⁵,aryl or aralkyl, which latter two groups are optionally substituted onthe aromatic ring by one or more groups independently selected from(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, hydroxy(C₁-C₆)alkyl,amino(C₁-C₆)alkyl, aryl, aralkyl, halo, hydroxyl, CO₂R^(7a),CONR^(8a)R^(9a), COR^(10a), SO₃G, SO₂NR^(11a)R^(12a), aryloxy(C₁-C₆)alkoxy, (C₁-C₆)alkylthio, —N═N—R^(13a), NR^(14a)R^(15a), or R¹and R² together with the ring to which they are bound represent asaturated or unsaturated carbocyclic or heterocyclic group containing upto three 3- to 8-membered carbocyclic or heterocyclic rings, whereineach carbocyclic or heterocyclic ring may be fused to one or more othercarbocyclic or heterocyclic rings, and wherein each of the rings may beoptionally substituted by one or more groups independently selected from(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, hydroxy(C₁-C₆)alkyl,amino(C₁-C₆)alkyl, aryl, aralkyl, halo, hydroxyl, COR^(7b),CONR^(8b)R^(9b), COR^(10b), SO₃G′, SO₂NR^(11b)R^(12b), aryloxy,(C₁-C₆)alkylthio, —N═N—R^(13b), NR^(14b)R^(15b) or (C₁-C₆)alkoxy; one ormore of R¹ to R⁶ optionally being covalently bonded via a carbon-carbon,carbon-nitrogen or carbon-oxygen bond to another R¹ to R⁶ group onanother compound of formula (I); R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴,R¹⁵, R^(7a), R^(8a), R^(9a), R^(10a), R^(11a), R^(12a), R^(13a),R^(14a), R^(15a), R^(7b), R^(8b), R^(9b), R^(10b), R^(11b), R^(12b),R^(13b), R^(14b) and R^(15b) are independently selected from H,(C₁-C₆)alkyl aryl or aralkyl; X is a neutral or negatively charged O-,N- or S-donor ligand or halo; G and G′ are independently selected fromalkali metals, aryl, aralkyl and (C₁-C₆) alkyl; Y is NR¹⁶R¹⁷ and Y′ isNR¹⁸R¹⁹, wherein R¹⁶, R¹⁷. R¹⁸ and R¹⁹ are independently selected fromH, (C₁-C₆)alkyl, aryl or aralkyl; L is 12-arylene,1,2-(C₅-C₈)cycloalkylene or (C₂-C₆)alkylene, provided that when L is(C₂-C₆)alkylene, one of R¹⁶ and R¹⁷ is covalently bonded to one of R¹⁸and R¹⁹ such that they form with L a ring containing Y and Y′, said1,2-arylene, 1,2-(C₅-C₈)cycloalkylene and (C₂-C₆)alkylene groups beingoptionally fused with one or more saturated or unsaturated carbocyclicor heterocyclic groups containing up to three 3- to 8-memberedcarbocyclic or heterocyclic rings, wherein each carbocyclic orheterocyclic ring may be fused to one or more other carbocyclic orheterocyclic rings, said 1,2-arylene, 1,2-(C₅-C₈)cycloalkylene and(C₂-C₆)alkylene groups and/or the groups to which they are fused beingoptionally substituted with one or more groups independently selectedfrom (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, hydroxy(C₁-C₆)alkyl,amino(C₁-C₆)alkyl, halo, hydroxyl, nitro, CO₂R^(7′), CONR^(8′)R^(9′),COR^(10′), SO₃H, SO₂N R^(11′)R^(12′), aryloxy, (C₁-C₆)alkoxy,(C₁-C₆)alkylthio, —N═N—R^(13′), NR^(14′)R^(15′), aryl or aralkyl, andhaving one or more CH₂ groups optionally replaced by C═O groups, whereinR^(7′), R^(8′), R^(9′), R^(10′), R^(11′), R^(12′), R^(13′), R^(14′) andR^(15′) are independently selected from H, (C₁-C₆)alkyl, aryl oraralkyl; m is −2, −1, 0, +1 or +2 and the compound comprises acounterion when m is not 0; the compound of formula (I) optionally beingin the form of a dimer in which two L groups are linked either directlyor through a group comprising one or more of (C₁-C₆)alkylene,(C₁-C₆)alkenylene, arylene, aralkylene, alkarylene, Se, Se—Se, S—S, N═Nand C═O or in which L bears two Y groups and two Y′ groups.
 16. Processfor preparing the compound of claim 1 which comprises the reaction of acompound of formula [(η⁶-C₆(R¹)(R²)(R³)(R⁴)(R⁵)(R⁶))RuX₂], optionally inthe form of a dimer, with Y-L-Y′, in a suitable solvent for thereaction, wherein R¹, R², R³, R⁴, R⁵, R⁶, X, Y, Y′ and L are as definedin claim 1.